Free radicals have long been postulated to contribute to neuronal injury in acute central nervous system injury, including stroke and trauma, and in the more chronic neurodegenerative diseases, including Parkinsons disease, multi-infarct dementia, and Alzheimers disease. These conditions are fast becoming the most pressing health care issues for the coming decades. Globally, 15% of the population over age 65 is reported as having some form of dementia, and current estimates in the U.S. place the number of affected individuals at well over 4 million, a number which may double or triple in the next 20 years (NIA Special Report, 1991; Odenheimer, 1989). In addition, cerebral infarction (stroke) is a leading cause of neurologic disability in the elderly. Yet, to date, there is no effective therapy to prevent or treat a majority of these neurologic disease states. The goal of the proposed project is to characterize free radical processes initiated by glutamate receptor overactivation (excitotoxicity), and to assess the contribution of free radicals to the death of neurons excitotoxicity. Glutamate is the major excitatory neurotransmitter in the brain, and is felt to play a major role in learning and memory. However, both free radical injury and glutamate receptor-mediated excitotoxicity are believed to contribute to the death of neurons in acute and chronic neurologic diseases, including stroke and head trauma, Parkinsons Disease, Huntingtons Disease, and possibly Alzheimers dementia. Production of free radicals, in particular hydroxyl radical, may be one key mechanism by which excitotoxicity results in irreversible neuronal damage. The hypothesis we will test is whether glutamate receptor activation can initiate hydroxyl radical production in neurons, and whether hydroxyl radical in turn is a component of glutamate neurotoxicity. This hypothesis will be tested using state-of-the-art methods for detecting free radicals, such as Electron Spin Resonance and High Performance Liquid Chromatography, to measure hydroxyl radical production during excitotoxicity in mouse brain cell cultures, together with pharmacologic and molecular biology approaches to altering free radical production and clearance. Clarifying the sources of free radicals and the events that trigger their production may assist in the development of rational treatment in neurologic diseases, including stroke and many forms of neurodegenerative diseases.